Meroterpenoids are hybrid natural products of both terpenoid and polyketide origin. We identified a biosynthetic gene cluster that is responsible for the production of the meroterpenoid pyripyropene in the fungus Aspergillus fumigatus through reconstituted biosynthesis of up to five steps in a heterologous fungal expression system. The cluster revealed a previously unknown terpene cyclase with an unusual sequence and protein primary structure. The wide occurrence of this sequence in other meroterpenoid and indole–diterpene biosynthetic gene clusters indicates the involvement of these enzymes in the biosynthesis of various terpenoid-bearing metabolites produced by fungi and bacteria. In addition, a novel polyketide synthase that incorporated nicotinyl-CoA as the starter unit and a prenyltransferase, similar to that in ubiquinone biosynthesis, was found to be involved in the pyripyropene biosynthesis. The successful production of a pyripyropene analogue illustrates the catalytic versatility of these enzymes for the production of novel analogues with useful biological activities.
- Structural biology and chemistry of the terpenoid cyclases. Chem. Rev. 106, 3412–3442 (2006).
- Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: logic, machinery, and mechanisms. Chem. Rev. 106, 3468–3496 (2006). &
- Meroterpenoids produced by fungi. Nat. Prod. Rep. 26, 1063–1097 (2009). &
- Pyripyropenes, highly potent inhibitors of acyl-CoA : cholesterol acyltransferase produced by Aspergillus fumigatus . J. Antibiot. 46, 1168–1169 (1993). , , &
- Pyripyropenes, novel inhibitors of acyl-CoA : cholesterol acyltransferase produced by Aspergillus fumigatus . J. Antibiot. 47, 148–153 (1994). , , , &
- Identification of the interaction site within acyl-CoA:cholesterol acyltransferase 2 for the isoform-specific inhibitor pyripyropene A. J. Biol. Chem. 283, 10453–10460 (2008). , , , &
- NMR assignments of territrems A, B, and C and the structure of MB2, the major metabolite of territrem B by rat liver microsomal fraction. J. Nat. Prod. 55, 251–255 (1992). , , &
- Arisugacins A and B, novel and selective acetylcholinesterase inhibitors from Penicillium sp. FO-4259. J. Antibiot. 49, 742–747 (1996). , , , &
- Territrem B, a tremorgenic mycotoxin that inhibits acetylcholinesterase with a noncovalent yet irreversible binding mechanism. J. Biol. Chem. 274, 34916–34923 (1999). , , , &
- Synthesis and biological activity of novel pyranopyrones derived from engineered aromatic polyketides. ACS Chem. Biol. 2, 104–108 (2007). &
- Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products. Nature 435, 983–987 (2005). , &
- Biosynthesis of a natural polyketide–isoprenoid hybrid compound, furaquinocin A: identification and heterologous expression of the gene cluster. J. Bacteriol. 188, 1236–1244 (2006). et al.
- A gene cluster for prenylated naphthoquinone and prenylated phenazine biosynthesis in Streptomyces cinnamonensis DSM 1042. ChemBioChem 7, 2016–2027 (2006). et al.
- Molecular basis for chloronium-mediated meroterpene cyclization. J. Biol. Chem. 282, 16362–16368 (2007). et al.
- Biosynthesis of pyripyropene A. J. Org. Chem. 61, 882–886 (1996). et al.
- Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438, 1151–1156 (2005). et al.
- Cloning of the polyketide synthase gene atX from Aspergillus terreus and its identification as the 6-methylsalicylic acid synthase gene by heterologous expression. Mol. Gen. Genet. 253, 1–10 (1996). et al.
- Product identification of polyketide synthase coded by Aspergillus nidulans wA gene. Tetrahedron Lett. 39, 7733–7736 (1998). et al.
- Re-identification of Aspergillus nidulans wA gene to code for a polyketide synthase of naphthopyrone. Tetrahedron Lett. 40, 91–94 (1999). et al.
- Heterologous expression and product identification of Colletotrichum lagenarium polyketide synthase encoded by the PKS1 gene involved in melanin biosynthesis. Biosci. Biotechnol. Biochem. 63, 1445–1452 (1999). et al.
- Enzymatic synthesis of 1,3,6,8-tetrahydroxynaphthalene solely from malonyl coenzyme A by a fungal iterative type I polyketide synthase PKS1. Biochemistry 39, 8853–8858 (2000). et al.
- Aspergillus fumigatus alb1 encodes naphthopyrone synthase when expressed in Aspergillus oryzae . FEMS Microbiol. Lett. 192, 39–44 (2000). et al.
- Identification of Claisen cyclase domain in fungal polyketide synthase WA, a naphthopyrone synthase of Aspergillus nidulans. Chem. Biol. 8, 189–197 (2001). , , &
- An iterative type I polyketide synthase PKSN catalyzes synthesis of the decaketide alternapyrone with regio-specific octa-methylation. Chem. Biol. 12, 1301–1309 (2005). , , , &
- Expression of Alternaria solani PKSF generates a set of complex reduced-type polyketides with different carbon-lengths and cyclization. ChemBioChem 7, 920–924 (2006). , , &
- GERI-BP001 compounds, new inhibitors of acyl-CoA : cholesterol acyltransferase from Aspergillus fumigatus F37. J. Antibiot. 48, 751–756 (1995). et al.
- Prenyl transfer to aromatic substrates: genetics and enzymology. Curr. Opin. Chem. Biol. 13, 171–179 (2009).
- Lewis acid-promoted intermolecular acetal-initiated cationic polyene cyclizations. J. Am. Chem. Soc. 129, 492–493 (2007). , &
- Four gene products are required for the fungal synthesis of the indole–diterpene, paspaline. FEBS Lett. 580, 1625–1630 (2006). , , &
- Molecular cloning and genetic analysis of an indole–diterpene gene cluster from Penicillium paxilli. Mol. Microbiol. 39, 754–764 (2001). , , &
- Indole–diterpene gene cluster from Aspergillus flavus . Appl. Environ. Microbiol. 70, 6875–6883 (2004). , , &
- Studies on biosynthetic genes and enzymes of isoprenoids produced by actinomycetes. J. Antibiot. 58, 227–243 (2005).
- Biomimetic total synthesis of the ACAT inhibitor (+)-pyripyropene E. Tetrahedron Lett. 37, 6461–6464 (1996). , , &
- Insight into steroid scaffold formation from the structure of human oxidosqualene cyclase. Nature 432, 118–122 (2004). et al.
- S14-95, a novel inhibitor of the JAK/STAT pathway from a Penicillium species. J. Antibiot. 56, 337–343 (2003). , , &
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